Abeta-immunotherapy has received considerable attention as a promising approach for reducing the level of the Abeta in the CNS of AD patients. However, the first clinical trial, AN 1792, was halted when a subset of those immunized with Abeta42 developed adverse events in the central nervous system, and data from the trial indicate that there was a low percentage of responders and generally low liters in the patients that received the vaccine. Overcoming the problems associated with inducing a safe, economical, and adequate immune response in elderly AD patients will require the development of suitable vaccine and strategies to avoid adverse events associated with immunized elderly AD patients. The goals for this proposal are to design a vaccine that is suitable for rapid translation to a clinical trial in AD patients, to identify risk factors associated with active and passive vaccination strategies using APP/Tg models, and to test neurovascular protective approaches as an addendum to immunotherapy. Accordingly, we have divided this competitive renewal application into three areas of focus (Aims) that collectively will help overcome the significant hurdles facing Abeta-immunotherapy: 1) To design and characterize the immune response to DNA and recombinant protein epitope vaccines composed of three copies of the major Abeta B cell epitope (Abeta1-11), a foreign promiscuous Th2 epitope (PADRE), and a robust Th2 molecular adjuvant, macrophage derived chemokine (MDC);2) To investigate the differences in clearance of Abeta and susceptibility to neurovascular pathology in old (16-20 months) and very old (20-24 months) APP/Tg2576 and Tg-SwDI mice after active or passive Abeta-immunotherapy;3) To investigate whether neurovascular protective strategies can attenuate the anti-Abeta antibody-induced microhemorrhages in APP/Tg 2576 and Tg- SwDI mice. The goals of this proposal are to develop a safe and effective vaccine for treating Alzheimer's disease. The vaccine is designed to use the patient's own immune system to clear the brain of a factor (beta-amyloid) that has been linked to the disease. Additional studies will focus on identifying risk factors associated with immunizing elderly patients and developing protective therapies to eliminate these risk factors.